Crystal modification

ABSTRACT

A novel crystal form of ,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneacetic acid hydrochloride, processes for its preparation and its pharmaceutical use are disclosed.

SUMMARY

[0001] This invention relates to a novel crystal form ofα,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneaceticacid hydrochloride, a process for its preparation and pharmaceuticalformulations thereof.

BACKGROUND

[0002] The compoundα,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneaceticacid hydrochloride has been named according to the U.S.A.N. asfexofenadine hydrochloride (“F-HCl”). It is known as the activemetabolite of the non-sedating antihistamine terfinadine and is itselfmarketed in the United States as a non-sedating antihistamine. F-HCl andits preparation are described, for example, in U.S. Pat. No. 5,578,610,which is here incorporated by reference. Anhydrous and hydrated crystalforms of F-HCl identified as Forms I, II, III and IV are described in WO95/31437.

[0003] The present invention relates to a novel F-HCl crystalmodification, hereinafter designated as Form A, which is distinguishedfrom previously known crystal forms by physical and spectroscopicproperties such as melting point, x-ray powder diffraction pattern,solid state NMR spectrum and infrared spectrum. The Form A crystalmodification of F-HCl is prepared in an advantageously environmentallyfriendly manner.

BRIEF DESCRIPTION OF THE DRAWINGS

[0004]FIG. 1 shows the powder x-ray diffraction pattern of the Form Acrystal modification of F-HCl (λ=1.540600).

[0005]FIG. 2 shows the solid state Carbon-13 NMR of the Form A crystalmodification of F-HCl over the chemical shift range of 275 to −100 ppm.

[0006]FIG. 3 shows the FTIR spectrum of the Form A crystal modificationof F-HCl as a mull with Nujol oil.

[0007]FIG. 4 shows the FTIR spectrum of Nujol oil.

DETAILED DESCRIPTION

[0008] The Form A crystal modification of F-HCl is characterized by itsphysical and spectroscopic properties which are described in detailbelow.

[0009] The Form A crystal modification of F-HCl has a characteristicmelting point in the range from about 138° C. to 148° C., morespecifically about 142° C. to about 145° C.

[0010]FIG. 1 is the powder x-ray diffraction pattern of the Form Acrystal modification of F-HCl. The powder x-ray diffraction pattern ofForm A is characterized by peaks at about 10.5, 8.1, 5.5, 5.4, 5.2,4.42, 4.15, 3.82, 3.35 d-spacing units. The x-ray diffraction patterndepicted in FIG. 1 is summarized in Table 1: TABLE 1 Powder X-RayDiffraction Peaks for the Form A crystal modification of F-HCl RELATIVERELATIVE Peak No. ° 2θ¹ d-space INTENSITY² Peak No. ° 2θ¹ d-spaceINTENSITY² 1 5.99 14.74 4 23 21.38 4.15 82 2 6.59 13.40 4 24 22.27 3.9828 3 6.83 12.91 9 25 22.68 3.91 27 4 8.42 10.49 45 26 23.29 3.81 33 59.09 9.71 7 27 24.82 3.53 9 6 9.47 9.32 23 28 25.03 3.55 9 7 10.85 8.1448 29 25.45 3.49 12 8 11.29 7.83 18 30 26.55 3.35 33 9 11.97 7.39 5 3127.50 3.24 11 10 12.45 7.09 4 32 29.09 3.06 6 11 13.26 6.66 26 33 30.312.94 13 12 13.67 6.46 31 34 31.40 2.34 17 13 14.80 5.93 7 35 31.82 2.815 14 15.08 5.86 6 36 33.34 2.68 5 15 15.54 5.69 9 37 35.66 2.51 5 1615.97 5.54 31 38 35.78 2.50 5 17 16.46 5.37 44 39 41.29 2.13 6 18 17.025.29 100 40 41.55 2.17 5 19 17.80 4.97 27 41 41.73 2.16 5 20 19.01 4.6526 42 42.90 2.13 9 21 20.05 4.42 36 43 43.09 2.09 9 22 20.57 4.31 19

[0011] Variances in the d-spacing values reported for any x-raydiffraction peak within ±1% are considered insignificant. The use of theexpression “about” when describing the position of an powder x-raydiffraction peak is intended to provide a basis for including suchinsignificant variances within the characterization of the Form Acrystal modification.

[0012]FIG. 2 shows the carbon-13 NMR spectrum of the Form A crystalmodification of F-HCl measured using 600 transients and a 6 second pulsedelay over the chemical shift range of 275 to −100 ppm. Characteristicsignals are observed at chemical shifts of 187.4, 180.3, 74.5, 48.8, and29.8 ppm. Table 2 summarizes the signals observed in the solid statecarbon-13 NMR of the Form A crystal modification of F-HCl. TABLE 2 SolidState NMR Signals of The Form A crystal modification of F-HCl peak#p.p.m. peak # p.p.m. 1 187.4 12 53.9 2 180.3 13 48.8* 3 148.3 14 43.2 4145.6 15 40.2 5 142.0 16 36.5 6 130.4* 17 32.9 7 128.2* 18 29.8 8 126.4*19 26.0* 9  78.9* 20 24.6* 10  74.5 21 22.6 11  57.5

[0013] The chemical shifts reported for solid state carbon-13 NMRsignals can vary from sample to sample by up to 1 ppm. The use of theexpression “about” to describe the chemical shift of an NMR signal isintended to include such variances within the characterization of theForm A crystal modification.

[0014] One more of the physical properties and/or spectroscopicproperties are the basis for characterizing the Form A crystalmodification of F-HCl.

[0015] For example, the Form A crystal modification of F-HCl is properlydescribed asα,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneaceticacid hydrochloride having a melting point in the range from 138° C. to148° C., or asα,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneaceticacid hydrochloride having a melting point in the range from about 142°C. to about 145° C. It is also properly described as crystallineα,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneaceticacid hydrochloride having powder x-ray diffraction peaks at d spacingsof 10.5, 8.1, 5.5, 5.4, 5.2, 4.42, 4.15, 3.82, 3.35 or the x-raydiffraction pattern depicted in Table 1. It is also properly describedasα,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneaceticacid hydrochloride having solid state carbon-13 NMR signals at chemicalshifts of 187.4, 180.3, 74.5, 48.8, and 29.8 ppm, or as having the solidstate carbon-13 NMR spectrum depicted in FIG. 2 and Table 2. It is alsoproperly described asα,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneaceticacid hydrochloride having the Fourier Transform Infrared Spectrumdepicted in FIG. 3A as a Nujol oil mull.

[0016] The Form A crystal modification is also properly described by acombination of physical and/or spectroscopic properties.

[0017] Thus, Form A F-HCl is a substantially pure crystal modificationofα,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneaceticacid hydrochloride characterized by powder x-ray diffraction peaks at dspacings of about 10.5, 8.1, 5.5, 5.4, 5.2, 4.42, 4.15, 3.82, 3.35 and amelting point in the range from about 142° C. to about 145° C.

[0018] Form A F-HCl is also a crystal modification ofα,α-dimethyl-4-{1-hydroxy-4-{4-hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneaceticacid hydrochloride characterized by solid state carbon-13 NMR signals atchemical shifts of about 187.4, 180.3, 74.5, 48.8, and 29.8 ppm andpowder x-ray diffraction peaks at d spacings of about 10.5, 8.1, 5.5,5.4, 5.2, 4.42, 4.15, 3.82, 3.35. It is also such a crystal modificationhaving a melting point in the range from about 142° C. to about 145° C.in pure form.

[0019] Form A F-HCl is also properly described as a crystal modificationhaving the solid state carbon-13 NMR spectrum depicted in FIG. 2 and thex-ray powder diffraction pattern depicted in FIG. 1. It is also such acrystal modification having the Fourier Transform Infrared Spectrumdepicted in FIG. 3A as a Nujol oil mull and can be further characterizedas having a melting point in the range from 138° C. to 148° C. insubstantially pure form, preferably from about 142° C. to about 145° C.in pure form.

[0020] Preferably, the Form A crystal modification of F-HCl is insubstantially pure form—substantially pure form being intended to meanthat at least 80 percent by weight of the crystalline F-HCl in thesample is present as Form A. Most preferably, the Form A crystalmodification is in pure form meaning that at least 90% of thecrystalline F-HCl in the sample is present as Form A. The presentinvention also relates to highly pure Form A crystal modificationmeaning that the material is essentially homogeneous Form A crystalmodification.

[0021] The Form A crystal modification of F-HCl is prepared in anenvironmentally friendly manner by crystallization from an aqueoussolution of F-HCl at a temperature in the range from 5° C. to 50° C.,preferably in the range from 20° C. to 40° C. Generally, a temperatureof about 30° C. is optimal. If the crystallization is carried out at thehigher and lower temperatures in the above defined temperature rangesthe resulting product can be a mixture of crystal forms which includesForm A.

[0022] Generally, crystalline or non-crystalline F-HCl is dissolved inwater with stirring to form an aqueous solution of F-HCl. Thetemperature of the aqueous solution of F-HCl is then adjusted to thedesired temperature range, for example, by placing it in a water or oilbath, the solution is stirred and the water allowed to partiallyevaporate to yield Form A crystals of F-HCl. Preferably, the evaporationof the water is assisted, for example, by passing a gentle stream of airover the surface of the solution or reducing the pressure above thesolution. However, the solution should be maintained in the temperatureranges identified above while the water evaporates from the solution.

[0023] Advantageously, no co-solvent or additional organic material ispresent in the water used to prepare the aqueous solution. However,minor amounts of such co-solvents or additional organic materials arenot known to cause any significant disadvantage.

[0024] Thus, the present invention relates to a method of preparing theForm A crystal modification ofα,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneaceticacid hydrochloride, which comprises preparing an aqueous solution ofα,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneaceticacid hydrochloride; and crystallizing theα,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneaceticacid hydrochloride from the aqueous solution at a temperature of from 5°C. to 50° C. Preferably, the crystallization is carried out at atemperature of 20° C. to 40° C. Optimally, the crystallization iscarried out at a temperature in the range from 25° C. to 35° C., mostoptimally at about 30° C.

[0025] The crystallization step is effected by methods known in the artfor precipitating a solute from solution, for example, by reducing thevolume of solvent by evaporation or other means, or by addition of aco-solvent which induces crystallization and seeding.

[0026] Preferably, the crystallization step is effected by reducing thevolume of water in the aqueous solution. Thus, the present inventionfurther relates to a process wherein the crystallization step iseffected by reducing the volume of water in the aqueous solution by anamount sufficient to promote crystallization. Preferably, the volume ofwater is reduced by evaporation of the water. This can be assisted byblowing a stream of air over the surface of the aqueous solution or byreducing the pressure above the solution in some other way.

[0027] The Form A crystal modification of F-HCl is used, in particular,for the preparation of pharmaceutical compositions of F-HCl. Thus, thepresent invention further relates to a pharmaceutical composition whichcomprises a pharmaceutically effective amount of the Form A crystalmodification ofα,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneaceticacid hydrochloride. Preferably, the pharmaceutically effective amount isthe amount required to deliver 50 to 150 mg/day.

[0028] The following example is intended to illustrate, but not limit,the invention. All melting points are uncorrected unless otherwisenoted.

EXAMPLE 1

[0029] A 0.51 gram sample of F-HCl (melting point range from 192° C. to198° C.) is dissolved in 100 mL of deionized water by heating on a waterbath at 80° C. and stirring at moderate speed with a 1 cm Teflon coatedmagnetic stirring bar. The temperature of the aqueous solution isreduced to 30° C. and held at that temperature in the water bath as agentle stream of air is passed over the surface. After about half of thewater evaporates (approximately 7 hours), the crystalline precipitate ofForm A F-HCl is separated by vacuum filtration with a Hirsch funnel. Thesample is protected from dust by a filter paper cover and allowed to dryin the air for approximately 48 hours.

[0030] The Form A F-HCl thus prepared exhibits a melting point of 142°C. to 145° C., determined in an open glass capillary suspended incirculating oil using a Thomas Hoover Melting Point Apparatus, thepowder x-ray diffraction pattern is depicted in FIG. 1 and Table 1, thesolid state carbon-13 NMR spectrum depicted in FIG. 2 and Table 2, andthe FTIR spectrum depicted in FIG. 3 as a Nujol mull.

We claim:
 1. The compoundα,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneaceticacid hydrochloride having a melting point in the range from 138° C. to148° C.
 2. The compoundα,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneaceticacid hydrochloride having a melting point in the range from about 142°C. to about 145° C.
 3. A crystal modification ofα,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneaceticacid hydrochloride characterized by powder x-ray diffraction peaks at dspacings of about 10.5, 8.1, 5.5, 5.4, 5.2, 4.42, 4.15, 3.82, 3.35. 4.The crystal modification of claim 3 having the powder x-ray diffractionpattern depicted in FIG.
 1. 5. The crystal modification of claim 3characterized by a melting point in the range from about 142° C. toabout 145° C.
 6. A crystal modification ofα,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneaceticacid hydrochloride characterized by solid state carbon-13 NMR signals atchemical shifts of about 187.4, 180.3, 74.5, 48.8, and 29.8 ppm.
 7. Thecrystal modification of claim 6 having the solid state carbon-13 NMRspectrum depicted in FIG.
 2. 8. The crystal modification of claim 6having powder x-ray diffraction peaks at d spacings of about 10.5, 8.1,5.5, 5.4, 5.2, 4.42, 4.15, 3.82, 3.35.
 9. The crystal modification ofclaim 8 having a melting point in the range from about 142° C. to about145° C.
 10. The crystal modification of claim 8 having a melting pointin the range from about 138° C. to 148° C.
 11. The crystal modificationof claim 7 having the powder x-ray diffraction pattern depicted inFIG.
 1. 12. The crystal modification of claim 11 having the FourierTransform Infrared Spectrum depicted in FIG. 3 as a Nujol oil mull. 13.The crystal modification of claim 12 having a melting point in the rangefrom about 138° C. to about 148° C. in substantially pure form.
 14. Thecrystal modification of claim 13 having a melting point in the rangefrom about 142° C. to about 145° C. in pure form.
 15. The crystalmodification of claim 14 in highly pure form.
 16. A process forpreparing the Form A crystal modification ofα,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneaceticacid hydrochloride, which comprises (a) preparing an aqueous solution ofα,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneaceticacid hydrochloride; and (b) crystallizing theα,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneaceticacid hydrochloride from the aqueous solution at a temperature of from 5°C. to 50° C.
 17. A process of claim 16 wherein the temperature is in therange from 20° C. to 40° C.
 18. A process of claim 17 wherein thetemperature is in the range from 25° C. to 35° C.
 19. A process of claim18 wherein the temperature is about 30° C.
 20. A process of claim 16wherein the crystallization step is effected by reducing the volume ofwater in the aqueous solution by an amount sufficient to promotecrystallization.
 21. A process of claim 19 wherein the crystallizationstep is effected by reducing the volume of water in the aqueous solutionby an amount sufficient to promote crystallization.
 22. A process ofclaim 21 wherein the volume of water is reduced by evaporation.
 23. Aprocess of claim 16 wherein theα,α-dimethyl-4-{1-hydroxy-4-{4-(hydroxydiphenylmethyl)-1-piperidinyl}butyl}benzeneaceticacid hydrochloride produced is pure Form A crystal modification.